Frailty represents the summation of the effects of motor neuron degeneration, muscle fiber denervation and degeneration, decreased muscle mass and strength, and mitochondrial dysfunction, but the cause-effect relationships among these variables are unknown. The primary long term goal of the Program Project is to understand the mechanisms underlying the age-related deterioration of motor nerves, muscle fibers, and mitochondria responsible for physical frailty. During our previous five years of support, dozens of knockout (KO) and over-expressor adult and old mice were investigated and superoxide-mediated oxidative stress was identified as a key factor in the age-related changes in the neuromuscular system. The Sod1-/- mouse was identified as the most promising animal model to test hypotheses regarding the role of oxidative stress in the age-related changes in nerves, neuromuscular junctions, muscle fibers, and mitochondria. In addition, CuZnSOD activity was rescued separately in nerves, Sod1-/-(N) mice, and muscles, Sod1-/-(M) mice, to address additional hypotheses related to the specific tissues in which oxidative stress is critical to the age-related changes. The three research groups in Ann Arbor, Liverpool and San Antonio have demonstrated their ability to collaborate with numerous meetings and the publication of major co-authored papers linking their expertise in physiology, biochemistry, molecular and cell biology, and bioengineering in the studies of the structure and function of muscles and mitochondria. The addition of Eva Feldman to Project 1 adds a further dimension in the fields of neurobiology and neurology for studies of the timing and interactions among age-related changes motor neurons, muscle fibers, and mitochondria. The Transgenic Animal Core in San Antonio has linked with that in Ann Arbor to facilitate the provision of KO and transgenic mice. The overall working hypothesis of the Program Project is that impaired regulation of superoxide in the Sod1-/- mouse leads to increased oxidative stress and damage in motor neurons, skeletal muscle fibers and mitochondria that cause acceleration in the development of age-related muscle atrophy and weakness. Testing this working hypothesis will provide insights into the underlying mechanisms associated with 'frailty'and 'failure to thrive'of elderly humans. The investigators in the three Projects have the diverse, well-established investigative skills, productivity, and proven ability in long term collaborations necessary to undertake this challenging task. The relevance to public health of the PPG lies in its focus on the major public health problem among the elderly of 'frailty and failure to thrive', estimated to cost $90 billion per year. Geriatricians cite a lack of understanding of the mechanisms underlying frailty as a major factor contributing to the lack of progress in the treatment of the condition. The scientific outcomes of this PPG should provide substantial scientific insights regarding the underlying causes of the condition and possible treatments.